Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins

J Cell Biol. 2009 Jun 1;185(5):797-810. doi: 10.1083/jcb.200810084. Epub 2009 May 25.

Abstract

Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1alpha and/or HP1gamma prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with "closed" telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antigens, Viral, Tumor / metabolism
  • Cell Line
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomal Proteins, Non-Histone / physiology*
  • Cyclin-Dependent Kinase 2 / analysis
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Humans
  • Nuclear Proteins / analysis
  • Nuclear Proteins / metabolism
  • RNA Interference
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 1 / analysis
  • Telomeric Repeat Binding Protein 2 / analysis
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Viral, Tumor
  • CBX5 protein, human
  • Chromosomal Proteins, Non-Histone
  • Cyclin-Dependent Kinase Inhibitor p21
  • Nuclear Proteins
  • PCNP protein, human
  • TERF2 protein, human
  • Telomeric Repeat Binding Protein 1
  • Telomeric Repeat Binding Protein 2
  • Tumor Suppressor Protein p53
  • Chromobox Protein Homolog 5
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2